ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6998C>A (p.Thr2333Lys)

dbSNP: rs150503164
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212056 SCV000149148 likely benign not provided 2021-05-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26787654, 24413734, 21665257, 19781682, 24618431, 25186627, 29522266)
Ambry Genetics RCV000115239 SCV000185041 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing The p.T2333K variant (also known as c.6998C>A), located in coding exon 47 of the ATM gene, results from a C to A substitution at nucleotide position 6998. The threonine at codon 2333 is replaced by lysine, an amino acid with similar properties. This alteration was detected in conjunction with a loss of function mutation in a family with ataxia-telangiectasia; however, information about the phase (cis vs trans) of these two alterations was not provided (Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128:382-9.e1). This alteration has been reported in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358), in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet., 2016 06;53:366-76), and was also detected on a 25-gene panel test in a woman of African ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001079437 SCV000254140 likely benign Ataxia-telangiectasia syndrome 2021-12-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115239 SCV000910893 likely benign Hereditary cancer-predisposing syndrome 2015-10-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201251 SCV001372353 likely benign not specified 2020-06-08 criteria provided, single submitter clinical testing Variant summary: ATM c.6998C>A (p.Thr2333Lys) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251024 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.6998C>A has been reported in the literature in individuals affected with Breast Cancer as well as in settings of multigene panel testing (example, Tung_2015, Young_2016). Additionally, this variant has also been reported in at-least one patient with Ataxia Telangiectasia (AT) who was compound heterozygous for two other deletrious variants in the ATM gene (Micol_2011). Although the phase of this variant relative to either of the deleterious variants was not provided, this finding supports a benign impact for this variant. Taken together, these report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or with AT. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV001201251 SCV002064679 uncertain significance not specified 2019-07-14 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115239 SCV002536842 likely benign Hereditary cancer-predisposing syndrome 2021-07-23 criteria provided, single submitter curation
Molecular Oncology - Human Genetics Lab,University of Sao Paulo RCV001843477 SCV002103139 uncertain significance Hepatoblastoma no assertion criteria provided research

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